Eligibility Criteria for Different Platinum-Based Chemotherapy Regimens in Metastatic Urothelial Carcinoma

Introduction Bladder cancer is one of the most prevalent cancers worldwide, with significant morbidity and mortality rates. Treatment options for metastatic urothelial carcinoma (mUC) primarily include platinum-based chemotherapy. Cisplatin-based chemotherapy is conventionally used for treating mUC, but many patients are ineligible due to various factors such as poor performance status, creatinine clearance, neuropathy, and cardiac function. Carboplatin-based therapy is another alternative, which typically yields less favorable outcomes. Some centers use split-dose cisplatin for treating patients with comorbidities and impaired renal function, broadening cisplatin’s spectrum. While eligibility criteria for full-dose cisplatin are well-established, those for split-dose cisplatin and carboplatin lack strong evidence. This study aims to assess the recommended criteria for full-dose cisplatin, split-dose cisplatin, and carboplatin regimens in real-world settings, including hematological parameters for patients with mUC. Methods A cross-sectional web-based survey was conducted among 136 oncologists from 21 countries, assessing criteria such as creatinine clearance, Eastern Cooperative Oncology Group (ECOG) performance status (PS), neurotoxicity, hearing loss, heart failure classification, and hematological parameters. Results The survey revealed diverse preferences among 113 oncologists treating mUC, regarding the eligibility criteria for each chemotherapy regimen with 81% prioritizing full-dose cisplatin, 21% split-dose cisplatin, and 14% carboplatin regimens. Criteria for all three regimens included specific thresholds. For full-dose cisplatin, the preferred criteria included creatinine clearance ≥60 mL/min, ECOG PS ≤1, grade 1 neuropathy, grade 1 deafness, New York Heart Association (NYHA) heart failure ≤class II with ≥50% cardiac ejection fraction, and normal blood parameters. Split-dose cisplatin criteria were creatinine clearance ≥40 mL/min, ECOG PS ≤2, grade 1 neuropathy, grade 1 deafness, NYHA heart failure ≤class II with ≥50% cardiac ejection fraction, and normal blood parameters. Carboplatin eligibility criteria were creatinine clearance ≥30, ECOG PS ≤2, grade ≤2 neuropathy, grade ≤2 deafness, NYHA heart failure ≤class II with ≥50% cardiac ejection fraction, and normal blood parameters. Hematological parameters were deemed crucial for all regimens, particularly stringent for carboplatin-based chemotherapy. Conclusion The study underscores the importance of renal function and hematological parameters in determining chemotherapy eligibility for patients with mUC. It highlights the importance of precise treatment criteria in mUC management, with hematological factors playing a significant role. Standardized criteria and further research are warranted to optimize treatment outcomes and minimize adverse events associated with chemotherapy regimens. Understanding the preferences of oncologists globally can facilitate tailored treatment approaches and improve patient care in the management of mUC.


Introduction
Bladder cancer ranks as the 10th most prevalent cancer worldwide and holds the sixth highest number of estimated cases among all cancers [1,2].It is the seventh most common cancer among men and ranks 17th among women [3].Bladder cancer can be categorized as urothelial or non-urothelial, including squamous cell carcinoma, adenocarcinoma, small cell carcinoma, or sarcoma [4].Urothelial carcinoma, originating from the urothelial cells, encompasses cancers of the urethra, bladder, ureter, and renal pelvis [5].Approximately 5-10% of urothelial carcinomas arise in the upper urinary tract (renal pelvis and ureter), while 90-95% occur in the lower tract (bladder and urethra) [1].Despite its prevalence, bladder cancer research progress has been limited over the past three decades.
Real-world studies indicate that 80-90% of patients with metastatic urothelial carcinoma (mUC) receive fulldose cisplatin chemotherapy as the conventional first-line treatment [1].A prospective phase II clinical trial (NCT01490437), examining the combination of pemetrexed and cisplatin in 42 patients with mUC having Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2, highlighted this regimen to be well-tolerated as a first-line treatment [6].In another phase II clinical trial (NCT01524991) with 36 chemotherapy-naive patients having mUC, the combination of gemcitabine-cisplatin plus ipilimumab demonstrated a 1-year overall survival rate of 61%, and a 69% objective response rate, with Grade ≥3 adverse events in 81% of patients, primarily hematologic [7].However, many patients are deemed ineligible based on various criteria like performance status, creatinine clearance, neuropathy, and cardiac function.
In several regions of the world, split-dose cisplatin is administered to full-dose cisplatin-ineligible patients with mUC to reduce renal toxicity [8,9].A phase II clinical trial (NCT04602078) explored the combination of atezolizumab, split-dose cisplatin, and gemcitabine in 66 patients with histologically confirmed mUC, suggesting potentially favorable outcomes compared to other combinations [10].Notably, split-dose cisplatin has also been employed in treating lung cancer [11].Alternatively, using carboplatin-based chemotherapy in patients ineligible for cisplatin yielded comparatively poor outcomes.In a randomized phase II study (EORTC 30986), gemcitabine-cisplatin was compared with gemcitabine-carboplatin in 238 chemotherapy-naïve patients with mUC having ECOG PS 2 and poor renal performance, revealing a comparably acceptable toxicity profile for gemcitabine-carboplatin [12].Decision-making in selecting treatment options for mUC relies on the Galsky and Bajorin risk factor criteria, but it deems patients ineligible for platinum-based chemotherapy [13].A similar scenario was observed in a survey-based study, where the criteria for patients ineligible for platinum-based chemotherapy were highlighted [14].Moreover, existing studies failed to address the hematological considerations necessary for holding patients eligible for platinum-based chemotherapy.The study aims to assess criteria, including hematological parameters, for initial treatment eligibility of mUC patients with full-dose cisplatin, splitdose cisplatin, and carboplatin-based chemotherapy.This includes gathering global uro-oncologists' opinions in a real-world context.

Study design and participants
A cross-sectional survey was conducted using an online questionnaire created in Microsoft Office Forms.The participants comprised practicing oncologists from various countries.The questionnaire was disseminated to approximately 1200 oncologists, via email for four months, from August to November 2023.The inclusion criteria mandated the active involvement of oncologists in treating patients with mUC.Oncologists not treating patients with mUC were excluded from the survey.
A team of experts from Saudi Arabia, specializing in treating patients with mUC, provided valuable inputs to originally develop the questionnaire (included in Table 1).It consisted of an initial consent section followed by four parts.The first part comprised eight questions related to basic demographics.Following that, the second, third, and fourth parts contained six questions each, assessing experiences regarding full-dose cisplatin eligibility, split-dose cisplatin usage, and carboplatin-based chemotherapy eligibility, respectively.The survey typically took about five minutes to complete.

Data collection and analysis
The online survey was structured with all mandatory fields, which rejected counting the partial and incomplete responses.Only complete responses were registered and subsequently considered for further calculations.The data collected from the responses were collated and descriptively analyzed.The responses entered by the participants in Microsoft Office Forms were automatically processed by Google Sheets, generating numbers, and graphs.The criteria for a parameter were chosen based on the option that received the highest response and was represented as count (n) and percentage (%), respectively.

Discussion
Bladder cancer imposes a significant burden on the healthcare system owing to its high prevalence and a 31-78% five-year recurrence rate after initial treatment [15].While men are 3-4 times more prone to developing bladder cancer, women experience a much worse prognosis [1].The five-year relative survival rate for individuals diagnosed with stage IV bladder cancer remains low, at approximately 15% [1].The Galsky and Bajorin risk factor criteria guide decision-making for treatment options in mUC, particularly deeming patients ineligible for platinum-based chemotherapy [13].

Parameters
In yet another study, the impact of the glomerular filtration rate on full-dose cisplatin-based neoadjuvant chemotherapy outcomes was investigated.Patients with normal glomerular filtration rate (≥60 mL/min) demonstrated a higher complete pathologic response rate (24% vs. 14%) than those with a lower glomerular filtration rate (34-59 mL/min).No significant glomerular filtration rate change was found after neoadjuvant chemotherapy [17].A 2022 survey with 60 oncologists identified ECOG PS and renal impairment as crucial factors in platinum ineligibility for mUC [14].The proposed updated criteria recommend ECOG PS >3, creatinine clearance <30 mL/min, peripheral neuropathy ≥Grade 2, and NYHA heart failure >Class III for platinum ineligibility, although age was not considered a significant criterion [14].Additionally, carboplatin was preferred for renal failure owing to its reduced nephrotoxicity.However, the lack of scientific evidence underscores the need to establish criteria for a carboplatin treatment regimen.
Evidence suggests that carboplatin has significantly lower nephrotoxicity and neurotoxicity than cisplatin.Studies comparing cisplatin and carboplatin chemotherapy regimens for mUC provide insights into the platinum eligibility criteria.A phase II study comparing carboplatin and cisplatin regimens for metastatic bladder cancer found that carboplatin has lower nephrotoxicity and neurotoxicity [18].Carboplatin showed an improved overall response rate with comparable progression-free survival and median overall survival.The thrombocytopenia was mild and reversible.Carboplatin was better tolerated with no severe nephrotoxicity discontinuations [18].In another comparative study, carboplatin and cisplatin showed no significant differences in overall response rate or complete responses [19].Despite the carboplatin group having more patients with advanced cancer experiencing bone metastasis, no renal toxicity was evidenced as compared to the cisplatin group.Furthermore, both groups had hematologic toxicities, but carboplatinassociated toxicities were more tolerable.Carboplatin-treated patients demonstrated better tolerance with similar outcomes to cisplatin-treated patients [19].In one study, carboplatin-treated patients showed better tolerance, fewer severe toxicities, similar overall response rate, overall survival, and progression-free survival outcomes than cisplatin-treated patients [20].Another study considering patients with adequate renal function and ECOG PS 0-2 found similar efficacy in advanced urothelial carcinomas, but carboplatin had fewer nephrotoxicity-related adverse events, suggesting that it may be a viable alternative, especially in cases of moderate renal failure [21].
Carboplatin is positioned as a less nephrotoxic substitute for renal-compromised patients than carboplatin [22][23][24].Carboplatin's pharmacokinetic profiles exhibit linear kinetics in individuals with creatinine clearances ≥60 mL/min [25,26].The reported total body clearance, apparent volume of distribution, and mean residence time were 73 mL/min, 16 L, and 3.5 hours, respectively [26,27].These pharmacological attributes contribute to the interest in carboplatin for its diminished nephrotoxicity and its predictable and consistent pharmacokinetic behavior, especially in patients with compromised renal function [25,27,28].
In our survey, the respondents preferred specific criteria based on the chemotherapy regimen for platinum eligibility.For full-dose cisplatin, they prioritized factors such as renal function, performance status, neuropathy, hearing levels, heart failure classification, and cardiac ejection fraction.Additionally, they emphasized the significance of normal hematological parameters, including hemoglobin, platelet count, and neutrophil count to be crucial.

Strengths and limitations
Despite providing valuable insights, this study has some limitations.The approach of self-reported data in survey-based studies may introduce bias, as respondents may provide information influenced by subjective interpretation.Additionally, despite extensive research on new oncology drugs in the United States, Europe, Canada, and Australia, responses from oncologists from these countries were limited (<20).The responses collated in this survey were predominantly from Asian oncologists.This is the main limitation of the survey in that it reflects the practice recommendations from a small number of oncologists, predominantly from Asia.This could affect the accuracy and reliability of the results.Further research integrating clinical outcomes and standardizing the criteria is essential for a comprehensive understanding of platinum-based chemotherapy in mUC.

Conclusions
This study highlights the importance of specific treatment criteria in managing bladder cancer, especially mUC.Oncologists prioritize parameters for each chemotherapy regimen, emphasizing renal function, performance status, and hematological factors for platinum eligibility.Hematological parameters play a crucial role in patient assessment.The findings contribute to the evolving mUC treatment landscape, emphasizing the need for tailored approaches aligned with global oncologists' perspectives.While carboplatin and cisplatin are established for front-line mUC treatment, studies support carboplatin as a less toxic alternative.Standardized criteria and larger samples are necessary for a more comprehensive understanding.

FIGURE 1 :FIGURE 2 :
FIGURE 1: Country of practice of the respondents

TABLE 2 : Demographic characteristics of the respondents
mUC: Metastatic Urothelial Carcinoma

TABLE 5 : Criteria for considering split-dose cisplatin in patients with mUC
ECOG PS: Eastern Cooperative Oncology Group Performance Status; mUC: Metastatic Urothelial Carcinoma; NYHA: New York Heart Association

TABLE 8 : Hematological criteria for considering carboplatin in patients with mUC
mUC: Metastatic Urothelial Carcinoma

TABLE 9 : Preferred platinum eligibility criteria for patients with mUC
Chosen criteria: This refers to the option that received the maximum preference from the respondents in the survey; ECOG PS: Eastern Cooperative Oncology Group Performance Status; mUC: Metastatic Urothelial Carcinoma; NYHA: New York Heart Association